Analysis of specific transcriptional regulators as early predictors of independent prognostic relevance in resected colorectal cancer.
Clin Cancer Res
; 13(4): 1123-32, 2007 Feb 15.
Article
em En
| MEDLINE
| ID: mdl-17317820
ABSTRACT
PURPOSE:
Prognostic studies on transcription factors acting at specific promoter elements have never been done so far. However, in tumors with long necessary follow-up, such as colorectal cancer, early-risk predictors would be needed. The invasion-related gene u-PAR is regulated via an activator protein 2 (AP-2)/Sp1 (-152/-135) and an AP-1 binding promoter motif (-190/-171), mediating u-PAR induction by K-Ras and Src. The present study was done to give first evidence for early prognostic relevance of transcription factors differentially bound to the u-PAR promoter, and their molecular inducers, in colorectal cancer. EXPERIMENTALDESIGN:
Tumor/normal tissues of 92 prospectively followed (median = 26.3 months) patients were analyzed for Src activity/protein, K-ras mutations, and transcription factor binding to both u-PAR promoter motifs (in vivo gel shift, kinase assay, and PCR).RESULTS:
Kaplan-Meier/Mantel-Cox analysis showed a significant correlation among elevated Sp1/Sp3 binding to region -152/-135 (P = 0.002 and P = 0.006), the combinations of Sp1/AP-2 and Sp1/AP-1 binding to both motifs (P = 0.010 and P = 0.005), and Sp1 binding/high Src protein in tumors (P < 0.001), with poor survival. Survival decreased with the number of bound transcription factors to both motifs, with binding of three factors defining a high-risk group (P = 0.021). In multivariate analysis, elevated Sp1 binding, combinations of Sp1/AP-2 binding and Sp1/AP-1 binding, or Sp1 binding/high Src were independent prognostic variables; u-PAR expression itself being not yet prognostic. A first molecular staging model (CART) was defined, providing novel early high-risk groups (mean survival time as low as for non-curatively resected patients) from these variables.CONCLUSIONS:
This study defines transcription factors acting at specific promoter elements of an invasion-related gene, mediating specific signaling, as novel, independent, early predictors of prognosis in colorectal cancer.
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Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Fatores de Transcrição
/
Neoplasias Colorretais
Tipo de estudo:
Prognostic_studies
/
Risk_factors_studies
Limite:
Female
/
Humans
/
Male
Idioma:
En
Ano de publicação:
2007
Tipo de documento:
Article